Transdermal Method and Patch for Nausea

ABSTRACT

Provided, among other things, is a method of treating acute, delayed or anticipatory emesis for a sustained period in an individual, which involves applying to a portion of intact skin on the individual a composition of 
         i. an antiemetically effective amount of a 5-HT 3  receptor antagonist; ii. a permeation enhancing amount of permeation enhancer comprising 0.5% to 15% by weight of the skin-contacting layer; and iii. an adhesive, 
 
wherein a plasma concentration of the 5-HT 3  receptor antagonist in a therapeutically effective range is provided for period of time from an onset time to 12 hours or more after the composition is removed.

This application claims the priority of U.S. Application 60/682,251,filed May 18, 2005, U.S. Application 60/702,744, filed Jul. 27, 2005,and U.S. Application 60/759,381, filed Jan. 17, 2006.

The present invention relates to a transdermal device and method for thetreatment of nausea and vomiting, and more particularly to a transdermalmethod, composition, and device containing a 5-HT₃ receptor antagonistfor the treatment of nausea and vomiting for a sustained period of time.

Most patients undergoing anticancer treatment either by chemotherapy orradiation suffer from side effects of the treatment such as nausea andvomiting, a common complaint by patients. To prevent or minimize theseside effects of anticancer treatments, antagonists of5-hydroxytryptamine subtype 3 (hereinafter referred to as ‘serotonin’)such as ondansetron, granisetron, tropisetron, dolasetron,hydrodolasetron, azasetron, ramosetron, lerisetron, indisetron,itasetron, palonosetron, lamosetron, allosetron and mixtures thereof,known as serotonin receptor antagonists or 5-HT₃ receptor antagonists,have been widely administered, either parenterally or orally, onmultiple days.

Nausea and vomiting may also occur due to other reasons, such as forexample, post-operatively, from motion sickness, or as a side effect ofother drugs taken by a patient. Examples of drugs which may cause nauseaand vomiting as side effects are certain antibacterial and antiviralagents, glucose-level-controlling bioactive agents, such as insulin andamylin or their natural and synthetic analogs, α-glucodase inhibitors,sulfonylurea, meglitinide, thiazolidinediones, biguanide, dualPPARα/γagonists, PPARγ agonists, and insulin secretagogues.

In any situation where a patient is suffering from nausea and vomiting,oral administration of an antiemetic agent is challenging and createsmore discomfort for the patient. Intravenous (IV) or intramuscular (IM)administration is generally impractical for home use. Oral, IM, and IVdosages must be given to the patient in multiple doses over time toachieve continuous antiemetic benefits, although these administrationroutes provide fluctuating plasma levels of the antiemetic agent.Additionally, since nausea and vomiting are challenging to reverse,antiemetic agents are most effective if given prophylactically.

To cope with these problems, there has been an attempt to formulate acomposition of an antiemetic agent in the form of patches so that theantiemetic agent can be administered transdermally.

Attempts to develop a transdermally administered antiemetic agent haveraised other problems. For example, some penetration enhancers used intransdermal compositions, (e.g., terpenes), induce skin irritation.Alcohols, which are often needed to solubilize the antiemetic agent fortransdermal applications, are also irritating to the skin. Also, becauseof rapid depletion of the alcohol, sustained delivery over a periodgreater than a few hours is difficult to achieve. When a transdermalcomposition consisting of a solution with a low viscosity is used, theblood level of the drug may easily drop below the effective level thuslessening the desired pharmacological effect.

Other efforts to administer antiemetic agents transdermally haveincluded complicated application devices or techniques such assupplemental energy to enhance the transdermal penetration of the drug.Current art describing transdermal antiemetic treatments often focuseson mimicking oral or IV agents to achieve therapeutic plasma levels.Typical delivery of such agents has been attempted with the salt form ofthe drug to maintain the stability of the active agent. However, saltforms of antiemetic agents have relatively low transdermalpermeabilities, and it is difficult to achieve therapeutic plasma levelsover a sustained period. Use of the free base form is typically notconsidered since it could be irritating or considered to be unstable inthe dosage form.

Thus, it is desirable to provide a transdermal composition of anantiemetic agent which is simple to use, nonirritating to the skin andwhich may be left in place on the skin for 24 hours, two days, threedays or more for continuously and effectively preventing, amelioratingor treating nausea and vomiting. Moreover, with modest but functionallysignificant concentrations of active and permeation enhancer, it isnonetheless possible using the current teachings to formulate a patchthat delivers antiemetic agent over a very substantial time period, andeven maintain delivery as measured at the blood level well after removalof the composition.

Extended delivery to the blood has been reported, but using transdermaldelivery devices that lacked permeation enhancer. See, WO 2004/069141.With the present invention, remarkably sustained delivery is achievedwith the presence of functionally significant concentrations ofpermeation enhancer. The lack of permeation enhancer is taught in the'141 application to limit instability and irritation. These samebenefits are achieved using the teachings of the current invention, butusing modest but functionally significant concentrations of permeationenhancer.

SUMMARY OF THE INVENTION

Provided in one embodiment is a method of treating acute, delayed oranticipatory emesis for a sustained period in an individual, the methodcomprising: applying to a portion of intact skin or mucosa on theindividual for 24 hours or more a composition comprising:

i. an antiemetically effective amount of a 5-HT3 receptor antagonist;

ii. a permeation enhancing amount of permeation enhancer comprising 0.5%to 15% by weight of the skin-contacting layer; and

iii. an adhesive,

wherein a plasma concentration of the 5-HT3 receptor antagonist in atherapeutically effective range is provided for period of time from anonset time to 12 hours or more after the composition is removed. Incertain embodiments, 12 or more hours after removing the composition,one applies a second said composition, wherein a plasma concentration ofthe 5-HT3 receptor antagonist in a therapeutically effective range isprovided for period of time from an onset time to 12 hours or more afterthe second said composition is removed.

In certain embodiments, the 5-HT3 receptor antagonist is administered inconjunction with another antiemetic agent, or the same agent in aseparate form of administration.

Additionally provided is a composition for transdermal administration ofan antiemetic comprising: a skin-contacting composition comprising:

i. an antiemetically effective amount of a 5-HT3 receptor antagonist;

ii. a permeation enhancing amount of permeation enhancer comprising 0.5%to 15% by weight of the skin-contacting layer; and

iii. an adhesive,

wherein, when applied to a portion of intact skin on an individual for24 hours (or more) and then removed, the composition provides theindividual with a plasma concentration of the 5-HT3 receptor antagonistin a therapeutically effective range for period of time from an onsettime to 12 hours or more after the composition is removed.

Further provided is a device for transdermal prevention, amelioration ortreatment of nausea and vomiting in an individual which comprises apatch comprising: (a) a support layer; and (b) a skin-contacting layercomprising:

i. an antiemetically effective amount of a 5-HT3 receptor antagonist;

ii. a permeation enhancing amount of permeation enhancer comprising 0.5%to 15% by weight of the skin-contacting layer; and

iii. an adhesive,

wherein, when applied to a portion of intact skin on an individual for24 hours (or more) and then removed, the device provides the individualwith a plasma concentration of the 5-HT3 receptor antagonist in atherapeutically effective range for period of time from an onset time to12 hours or more after the device is removed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the in vitro flux of granisetron through humancadaver skin using an embodiment of a device of the present invention.

FIG. 2 is a graph of the in vitro cumulative delivery of granisetronthrough human cadaver skin using an embodiment of a device of thepresent invention.

FIG. 3 shows a pharmacokinetic profile obtained using a device of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “5-HT₃ receptor antagonist” refers to any of aclass of drugs which act as 5-hydroxytryptamine receptor antagonists toprovide an anti-nausea and anti-vomiting effect in individuals.

As used herein, the term “antiemetic” refers to the prevention,amelioration or treatment of nausea and vomiting in individuals.

As used herein, the term “antiemetic agent” refers to a drug or materialthat is used to prevent, ameliorate or treat nausea and vomiting inindividuals.

As used herein, the term “antiemetically effective amount” refers to thedose or blood level (depending on the context) of an antiemetic agentthat provides relief from (including amelioration of) nausea andvomiting in an individual. In the case of blood levels, the level that,if appropriately sustained, provides relief from (including ameliorationof) nausea and vomiting in an individual. The amount is an amount thatcan be expected to be effective in segment(s) of a targetedpatient/subject population, and can be such an amount divided by areasonable number of delivery devices or vehicles.

As used herein, the term “individual” refers to a living mammal andincludes, without limitation, humans and other primates, livestock andsports animals such as cattle, pigs and horses, and pets such as catsand dogs.

As used herein, the term “onset time” refers to the time afterapplication of the transdermal device or composition to an individualuntil an antiemetically effective amount is obtained in the individual'sblood.

As used herein, the term “permeation enhancement” refers to an increasein the permeability of skin to a therapeutic agent in the presence ofpermeation enhancer(s) as compared to permeability of skin to the sametherapeutic agent in the absence of a permeation enhancer(s).

As used herein, the term “permeation enhancer” refers to an agent or amixture of agents which acts to increase the permeability of the skin totherapeutic agents.

As used herein, the term “permeation-enhancing amount” refers to anamount of a permeation enhancer which provides permeation enhancementthroughout a substantial portion of the administration period.

As used herein, the phrase “portion of intact skin” refers to a definedarea of intact unbroken skin or mucosal tissue. That area will usuallybe in the range of about 5 cm² to about 100 cm².

As used herein the term “salt” refers to, but is not limited to,pharmaceutically acceptable organic or inorganic salts. Typicalinorganic salts include hydrogen halides such as hydrochlorides,carbonates, phosphates, sulfates, hydrogen sulfates, hydrobromides,nitrates, and sulfides. Organic salts include, but are not limited to,acid addition salts including salts of monocarboxylic and polycarboxylicacids such as acetic acid, malic acid, maleic acid, propionic acid,succinic acid, fumaric acid, citric acid, benzoic acid, cinnamic acid,tartaric acid, and the like.

As used herein, the phrase “sustained time period” refers to about 24hours or more and will typically intend a period in the range of about48 or 72 hours to 168 hours.

As used herein, the term “transdermal” refers to both percutaneous andtransmucosal administration, i.e., passage of a drug, such as anantiemetic agent through a body surface or membrane such as intactunbroken skin or intact unbroken mucosal tissue into the systemiccirculation.

As used herein, the phrase “transdermal device wear time,” or “patchwear time” refers to the interval of time during which a transdermaldevice is maintained in place on a portion of an individual's skin ormucosa.

As used herein, the term “percutaneously absorbable” refers to theability of a drug to pass through a body surface or membrane such asintact unbroken skin or mucosal tissue into the circulation system whenformulated in a transdermal device of the invention.

As used herein, the term “acute nausea and vomiting” relates to nauseaand vomiting in an individual lasting up to 24 hours after theindividual receives chemotherapy, radiation, or drug treatment. It mayalso relate to post-operative nausea and vomiting and to nausea andvomiting resulting from motion sickness.

As used herein, the term “delayed nausea and vomiting” relates to nauseaand vomiting in an individual occurring up to five (5) days after theindividual receives chemotherapy, radiation, postoperatively or postdrug treatment.

As used herein, the term “anticipatory nausea and vomiting” relates to aconditioned response in an individual after the individual receiveschemotherapy, radiation, or drug treatment if the individual expects toexperience nausea and vomiting as a result of the treatment or if theindividual experienced nausea and vomiting as a result of previoustreatments. Anticipatory nausea and vomiting may also be experiencedpost-operatively or as a result of motion sickness.

As used herein, the term “skin-contacting layer” is a layer of atransdermal device for contacting skin or mucosa.

As used herein, “flux rate” means the rate as modeled from applicationsof the device to human cadaver skin.

The present invention relates to methods of preventing, ameliorating ortreating nausea and vomiting for a sustained time period by thetransdermal administration of transdermal device, the free base form of5-HT₃ receptor antagonists, examples of which antiemetic agents. Theantiemetic agents used in the present invention are, in the includeondansetron, granisetron, tropisetron, dolasetron, hydrodolasetron,azasetron, ramosetron, lerisetron, indisetron, itasetron, palonosetron,lamosetron, allosetron and mixtures thereof. It will be recognized thatafter administration the antagonists will form similar salts ormetabolites as are formed given other means of administration or theadministration of salt forms. The present invention also relates todevices and compositions for use with the method of the invention.

The method of the present invention is effective in the prevention,amelioration or treatment of nausea and vomiting due to chemotherapy,radiation therapy, other drug therapy, motion sickness, orpost-operative reaction. Because this method involves the transdermaladministration of an antiemetic agent over the course of days, it iseffective in preventing, ameliorating or treating nausea and vomitingfor an extended time. Additional benefits of the present inventioninclude improved patient compliance, since the method involves theplacement of a transdermal device, which in some embodiments is left inplace for 2, 3, 4, 5, 6, 7 days or more; patient protection from nauseaand vomiting from the time the device is applied until it is removed, orfor extended periods, such as 6, 9, 12, 18 or 24 hours or more, after itis removed; increased patient confidence to leave the hospital ordoctor's office after chemotherapy, knowing that the device will preventor reduce nausea and vomiting. Additionally, the device can maintainblood levels of the antiemetic agent in a therapeutically effectiverange until it is removed. In some embodiments, after wearing the devicefor 24 hours or more (or 36 hours or more, or 48 hours or more, or 72hours or more), blood levels are maintained in therapeutically effectiverange for an extended period after removal, such as 6, 9, 12, 18 or 24hours or more. Since the device delivers the antiemetic agent at acontrolled rate, there is no initial spike in plasma concentration aswhen the agent is administered, for example, by IV; therefore, themethod reduces side effects, such as headache and constipation,sometimes experienced with other forms of administration.

In certain embodiments, therapeutically effective blood levels of 5-HT₃receptor antagonist are obtained within 24 hours of application, 18hours of application, 12 hours of application, or within 9 hours, orwithin 8 hours, or within 7 hours, or within 6 hours. Such onset periodswill vary with the 5-HT₃ receptor antagonist and the particularskin-contacting layer formulation.

In certain embodiments, the patch provides a flux rate of 1 μg/cm²/hr ormore (such as between 1 and 25 μg/cm²/hr) of the 5-HT₃ receptorantagonist for, after an onset period, 24 hours or more, 48 hours ormore, or 72 hours or more, or 96 hours or more, or 120 hours or more, or144 hours or more, or 168 hours or more. In certain embodiments, thepatch provides a flux rate of 2 μg/cm²/hr or more (such as between 2 and10 μg/cm²/hr) of the 5-HT₃ receptor antagonist for, after an onsetperiod, 24 hours or more, 48 hours or more, or 72 hours or more, or 96hours or more, or 120 hours or more, or 144 hours or more, or 168 hoursor more.

In certain embodiments, the patch delivers between 10 μg/day(microgram/day) or more (such as 10 to 10,000 μg/day) of the 5-HT3receptor antagonist to the individual for, from an onset time to 24hours or more, 48 hours or more, or 72 hours or more, or 96 hours ormore, or 120 hours or more, or 144 hours or more, or 168 hours or more.In certain embodiments, the patch delivers between 20 μg/day(microgram/day) or more, or 50 μg/day or more, 100 μg/day or more, 200μg/day or more, 500 μg/day or more, 1,000 μg/day or more, 2,000 μg/dayor more, 4,000 μg/day or more, 6,000 μg/day or more, of the 5-HT3receptor antagonist to the individual for, from an onset time to 24hours or more, 48 hours or more, or 72 hours or more, or 96 hours ormore, or 120 hours or more, or 144 hours or more, or 168 hours or more.It will be recognized that the amount sought to be delivered will varywith the 5-HT3 receptor antagonist. For example, with ondansentronamounts may need to be higher than for granisetron.

The permeation enhancer used in the device of the present invention canact to increase the permeability of the skin to the 5-HT₃ receptorantagonist in the skin-contacting layer. In general, the higher theamount of permeation enhancer, the greater the increase in the skin'spermeability; however, at higher amounts of permeation enhancer, coldflow of the adhesive can also occur, making it necessary to remove thetransdermal patch prematurely. “Cold flow” is the phenomenon of lateralflow of the reservoir material from under its backing layer or the like.Also at higher amounts of permeation enhancer, the 5-HT₃ receptorantagonist may crystallize out of the matrix, thus limiting itspermeability. Therefore, it is desirable to use an amount of permeationenhancer which will reliably enhance the drug's permeability while stilllimiting or preventing adhesive cold flow and drug crystallization. Inone embodiment of the device of the present invention, the permeationenhancer in an amount of 15% or less (or about 14% or less, or about 13%or less, or about 12% or less, or about 11% or less, or about 10% orless, or about 9% or less) of the weight of the skin-contacting layer(or composition) to enhance the permeability of the drug without causingsignificant adhesive cold flow or drug crystallization. The permeationenhancer is present in a permeation-enhancing amount. The permeationenhancer can be present, for example, in an amount of about 0.5% or more(or about 1% or more, or about 2% or more, or about 3% or more, or about4% or more, or about 5% or more, or about 7% or more) of the weight ofthe skin-contacting layer (or composition)

The amount of 5-HT₃ receptor antagonist can be varied, for example, fromabout one of the lower limits described below (with the limit exclusiveor inclusive of the endpoint), or from to one of the upper limits(exclusive or inclusive). The lower limits are, based on the weight ofthe skin contacting layer or the composition, 0.1%, 0.2%, 0.5%, 1%, 2%,3%, or 4%. The upper limits are, based on the weight of the skincontacting layer or the composition, 15%, 14%, 13%, 12%, 11%, 10%, 9%,8% 7% or 6%. Again, these amounts may additionally vary with theparticular 5-HT3 receptor antagonist.

One embodiment of the device of the present invention is a transdermalpatch for application to the skin or mucosa of an individual. The patchhas a skin or mucosa-contacting layer (“skin-contacting layer” forsimplicity) laminated or otherwise attached to a support layer.Typically, the skin-contacting layer is covered by a removable releaseliner before use to protect the skin-contacting surface and keep itclean until it is applied to the skin or mucosa.

The support layer acts as a support for the skin-contacting layer andprovides a barrier layer that prevents loss of the drug in theskin-contacting layer to the environment. The material chosen for suchsupport should be compatible with the adhesive, drug, and permeationenhancer, and should be minimally permeable to any components of thepatch. The support can be opaque to protect components of the matrixpatch from degradation from exposure to ultraviolet light. Further, thesupport should be capable of binding to and supporting the adhesivelayer, yet should be pliable to accommodate the movements of a personusing the patch. Suitable materials for the carrier include metal foils,metalized polyfoils, composite foils or films containing polyester suchas polyester terephthalate, polyester or aluminized polyester,polytetrafluoroethylene, polyether block amide copolymers, polyethylenemethyl methacrylate block copolymers, polyurethanes, polyvinylidenechloride, nylon, silicone elastomers, rubber-based polyisobutylene,styrene, styrene-butadiene and styrene-isoprene copolymers,polyethylene, and polypropylene. A thickness of about 0.0005 to 0.01inch can, for example, be used. The release liner can be made of thesame materials as the carrier, or other suitable films coated with anappropriate release surface.

If present, the permeation enhancer is typically a fatty acid ester offatty acyl chain length C₁₂-C₁₈. The alcohol component of the ester istypically C1-C6, or C2-C4, such as for example isopropanol.

The patch can further comprise various additives in addition to theadhesive, antiemetic, and permeation enhancer. These additives aregenerally those pharmaceutically acceptable ingredients that are knownin the art of drug delivery and, more particularly, in the art oftransdermal drug delivery. Nonlimiting examples of additive ingredientsinclude diluents, excipients, emollients, plasticizers, skin irritationreducing agents (which can also include agents that reduce irritation tomucosa), carriers, and mixtures of these. For example, suitable diluentscan include mineral oil, low molecular weight polymers, plasticizers,and the like. Many transdermal drug delivery formulations have atendency to cause irritation after prolonged exposure to the skin ormucosa, thus addition of an irritation reducing agent aids in achievinga composition that is better tolerated by the skin or mucosa.

For delivery of the antiemetic agent according to an embodiment of thepresent invention, a patch device containing an adhesive, a 5-HT3receptor antagonist, and a permeation enhancer is brought in contactwith the skin or mucosa at a selected portion of intact skin or mucosaand is held in place by the adhesive.

In certain embodiments, the transdermal composition (prior toapplication to a patient) is essentially free of water. In certainembodiments, the transdermal composition is essentially free oftetraglycol (also known as glycofurol ortetrahydrofurfurylpolyethilenglycole). In certain embodiments, thetransdermal composition is essentially free of a hydrophilic organicsolvent, including essentially free of ethanol, isopropanol, butanol,benzyl alcohol, propylene glycol, glycerin, polyethylene glycol having amolecular weight of 600 or less, diethylene glycol monoethyl ether,triacetin, N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide,decylmethyl sulfoxide, dioxane, lactone or mixtures thereof. For thepurposes of the preceding proviso, “hydrophilic organic solvent” doesnot include fatty acid esters of fatty acyl chain length C12-C18. Itwill be understood that nominal amounts of such components, when thetransdermal composition is essentially free thereof, may be present inamounts consistent with process parameters, but are not present inamounts having a material effect on function, handling, storage, or somefactor material to the effective use or marketing of a transdermaldevice.

In another embodiment the present invention provides a method for theprevention, amelioration or treatment of nausea and vomiting due tochemotherapy, radiation therapy, other drug therapy, motion sickness, orpost-operative reaction by the transdermal administration of a 5-HT₃receptor antagonist combined with the administration (e.g., oral,injection (such as IV, IP, IM, SC), transdermal, buccal, rectal) ofanother antiemetic agent (e.g., a corticosteroid), or the same 5-HT₃receptor antagonist administered by separate administration route. Asecond administration form can be administered by a separate dosingschedule, as appropriate for the given dosage form.

Concurrent administration of 5-HT₃ receptor antagonists andcorticosteroids for the treatment of nausea and vomiting is known. Forexample, U.S. Pat. No. 5,929,059 (Sanger et al.) discloses a method oftreatment and/or prophylaxis of nausea and vomiting, which comprisesadministering to a human or animal subject, granisetron and steroid suchas dexamethasone or a pharmaceutically acceptable salt or ester thereof.Sanger et al. further disclose that these two ingredients may beadministered orally, rectally, parenterally, or buccally, with oraladministration being preferred.

However, as earlier described herein, oral administration of anti-emeticcompounds can be challenging and may lead to greater discomfort for thepatient. Additionally, oral, IV, IM, rectal, and buccal administrationof active ingredients produce fluctuation in plasma levels of the activeingredients. Therefore, it would be advantageous to transdermallyadminister a 5-HT₃ receptor antagonist, thus preventing, ameliorating,or treating nausea and vomiting, and then to administer anantiemetically effective amount of an antiemetic corticosteroid, whichcan enhance the antiemetic properties of the 5-HT₃ receptor antagonist.The antiemetic corticosteroid administration can be started at the sametime as the beginning of the transdermal administration of the 5-HT₃receptor antagonist or after the 5-HT₃ receptor antagonist has beentransdermally administered for one hour or more, 12 hours or more, or 24hours or more. Administrations can be maintained for 12 hours or more,or 24 hours or more, 48 hours or more, 72 hours or more, 96 hours ormore, 120 hours or more, 144 hours or more, or 168 hours or more. Thecorticosteroid administration may occur as a single dosage or additionaldosages may be administered at selected intervals. Useful routes ofadministration include, for example, oral or parenteral routes.

Antiemetic corticosteroids suitable for use in this embodiment of theinvention can include, for example, dexamethasone, methylprednisolone,prednisolone, their physiologically acceptable salts or esters, orcombinations thereof. Dexamethasone may be administered as dexamethasonealcohol or in the form of a pharmaceutically acceptable salt or ester.Suitable salts and esters include the acetate, isonicotinate,phenylpropionate, pivalate, t-butyl acetate, trioxaundecanoate, disodiummetasulphabenzoate and disodium phosphate.

A dose of steroid such as dexamethasone for use according to the methodof this embodiment of the invention can, for example, be in the range of0.5 to 20 mg per dosage unit. The unit doses may be administered from 1to 4 times per day. However, the exact dose will depend on the route ofadministration and the condition being treated, and it will beappreciated that it may be necessary to make routine variations to thedosage depending on the age and weight of the patient, as well as thenature and severity of the condition being treated.

Compositions for oral administration of dexamethasone, such as tabletsand capsules, may be prepared by conventional means withpharmaceutically acceptable excipients such as binding agents (e.g.pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricant (e.g. magnesium stearate, talc orsilica); disintegrants (e.g. potato starch or sodium starch glycollate);or wetting agent (e.g. sodium lauryl sulphate). Tablets may be coated bymethods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g. sorbitol syrup,cellulose derivatives or hydrogenated edible fats); emulsifying agents(e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oilyesters, ethyl alcohol or fractionated vegetable oils); and preservatives(e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, flavoring, coloring andsweetening agents as appropriate.

Preparations for oral administration of the corticosteroid may besuitably formulated to give controlled release of the active ingredient.

For parenteral administration the compositions may be presented in aform suitable for bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in syringes,ampoules or in multi-dose containers, with an added preservative. Thecompositions may take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredients may be in powder form for constitution with asuitable vehicle, e.g. sterile pyrogen-free water, before use.

In certain embodiments of this invention a transdermal patch with askin-contacting layer comprising:

-   -   i. an antiemetically effective amount of a free base of a 5-HT₃        receptor antagonist;    -   ii. a permeation-enhancing amount of a permeation enhancer        selected from the group consisting of isopropyl myristate,        isopropyl palmitate or fatty acid esters of fatty acyl chain        length C12-C18; and    -   iii. an adhesive selected from the group consisting of acrylics        (including alkyl acrylics), vinyl acetates, natural and        synthetic rubbers, ethylenevinylacetate copolymers,        polysiloxanes, polyacrylates, polyurethanes, plasticized        polyether block amide copolymers, plasticized styrene-butadiene        rubber block copolymers, and mixtures thereof,        is applied to the skin or mucosa of an individual in need of        anti-emetic treatment or prevention. Subsequently, an        antiemetically effective amount of a systemic corticosteroid is        orally administered to the individual to enhance the antiemetic        effectiveness of the 5-HT3 receptor antagonist.

In a further embodiment, the transdermal device is provided togetherwith a systemic corticosteroid, such as dexamethasone, in the form of akit.

In another embodiment the present invention provides a method for theprevention, amelioration or (including amelioration of succeedingsymptoms following prophylactic administration) or treatment of nauseaand vomiting due to chemotherapy, radiation therapy, other drug therapy,motion sickness, or post-operative reaction by the transdermaladministration of a 5-HT₃ receptor antagonist combined with the oral oradministration by injection of antiemetic agent(s). The antiemetic agentcan be selected from the group consisting of 5-HT₃ receptor antagonists,cannabinoids, NK1 receptor antagonists, dopamine antagonists,corticosteroids, or any other known antiemetic agent. In certainembodiments, the antiemetic agent is administered to the individual atthe same time that the transdermal device is applied to the individual'sskin. In other embodiments, other antiemetic agent(s) are administeredwith a timing selected to provide an initial delivery to plasma duringthe lag phase of the transdermal administration.

In one embodiment the transdermal device is provided with an antiemeticagent in the form of a kit. In a further embodiment, the kit compriseslabeling describing administering the antiemetic agent to the individualat about the same time that the transdermal device is applied to theindividual's skin. Examples of the second component include a dosageform comprising the same or a separate antiemetic agent as in the firsttransdermal device. The second dosage form can be, for example, foradministration orally, by injection (such as IV, IP, IM, SC),transdermally, buccally, rectally, or the like.

In another embodiment, the transdermal device is applied to theindividual's skin up to, for example, 24 hours before the individual isto be subjected to an event that creates a risk of emesis. Such eventsinclude administration of a pharmaceutical compound that creates a riskof emesis, such as, for example, chemotherapeutic agents for anticancertherapy, and surgical or other medical procedures that create a risk ofemesis. In a further embodiment, the transdermal device is applied tothe individual's skin 0.5 or more hours (1 or more hours, or 2 or morehours, or 4 or more hours, or 8 or more hours, or 10 or more hours, or12 or more hours) before the individual is to be subjected to an eventthat creates a risk of emesis.

In other transdermal devices adapted to give long-term delivery ofgranisetron, such long term delivery is achieved by avoiding permeationenhancers. The current invention provides a device that includes suchenhancer, but nonetheless provides long term delivery, while at the sametime avoiding irritation and instability that can be associated withenhancers. Moreover, in certain embodiments the current device provides,on a device area-normalized basis, greater transdermal delivery to theplasma as measured by peak plasma levels or AUC (area under the curve)than a device that corresponds in all but the absence of permeationenhancer. In certain embodiments, such delivery is 1.5 times or more, or1.7 times or more, or 2 times or more, as measured at 24, 48, 72, 96 or120 hours after application of the device.

EXAMPLE 1 Preparation of Adhesive Mixture and Transdermal DeliveryDevice

TABLE 1 Composition Formulation A Formulation B Patch Size 15.0 cm² 15.0cm² Estimated Target Daily 1.2 mg 1.2 mg Dose Dry % Dry %Styrene-butadiene rubber 44.04 — pressure sensitive adhesiveAcrylate-vinylacetate — 43.8 pressure sensitive adhesive IsopropylMyristate 3.01 4.07 Granisetron Base 3.05 3.05 Polyester Release liner35.8 35.8 Polyester Backing 13.3 13.3Components

Formulation A and Formulation B were prepared using the amounts of eachcomponent as shown in Table 1 above.

The styrene-butadiene rubber pressure sensitive adhesive used in theexamples herein was DURO-TAK®87-6173 adhesive, available from NationalStarch and Chemical in Bridgewater, N.J. The acrylate-vinylacetatepressure sensitive adhesive used in the examples herein wasDURO-TAK®87-2516 adhesive, available from National Starch and Chemicalin Bridgewater, N.J. The isopropyl myristate used in the examples hereinwas of NF grade. The polyester release liner used in the examples hereinis available from Loparex, Inc., and the polyester backing used in theexamples herein is available from 3M as 2610F.

Procedure

The granisetron base is dissolved in an appropriate solvent such astoluene and mixed with the selected adhesive. The isopropyl myristate isthen added to the mixture and the contents are mixed until a homogeneoussolution is achieved.

The homogeneous solution is coated onto the siliconized surface of thepolyester release liner to the desired thickness. The coated releaseliner is then passed through a drying oven until the solvents areevaporated. The dry adhesive-coated release liner is removed from theoven and is then laminated with the polyester backing layer. Themulti-layer laminate is cut by punching out units of the desired sizeand geometry for delivery of the desired target daily dose, or it may bewound into rolls for storage or transport to another location. Therolled laminate may then be unwound and cut by punching out units of thedesired size and geometry. These punched units are then placed inindividual pouches and sealed for later use as patches.

Irritation Data

Formulation A was tested in a rabbit irritation test, a guinea pigsensitization test, a dog toxicokinetic and a human irritation test, andfound non-irritating and non-toxic.

EXAMPLE 2 Test for Flux of Granisetron from the Transdermal DeliveryDevice

Procedure

Heat-separated human cadaver skin was cut to the desired size andmounted on a Franz diffusion cell. The release liner was peeled awayfrom a patch made according to Formulation B as described in EXAMPLE 1above. The patch was placed on the skin and the patch and skin wereclamped together. Receptor solution was added to the diffusion cell, andthe assembly was maintained at 32° C. Aliquots of the receptor solutionwere taken at periodic time points (24 hours, 48 hours, 72 hours, 96hours, and 120 hours). The concentration of the granisetron in thereceptor solution was measured at each time point, and the flux ratefrom examples A and B was calculated. The resulting data is illustratedin FIG. 1. Cumulative delivery of granisetron over the indicated timewas likewise calculated from the concentration of granisetron in thereceptor solution at each time point and is illustrated in FIG. 2.

EXAMPLE 3 Stability of Granisetron in Illustrative Examples

TABLE 2 Formulation C Formulation D Composition Dry % Dry %Styrene-butadiene rubber 49.88%  — pressure sensitive adhesiveAcrylate-vinylacetate 43.77%  pressure sensitive adhesive IsopropylMyristate — 5.09% Granisetron Base* 1.02% 2.04% Polyester Release liner35.8% 35.8% Polyester Backing 13.3% 13.3%

Patches were made according to the procedure described in Example 1above using the formulations shown in Table 2. The patches were thentested for granisetron stability using the method described below.

Samples of the patches are stored at 50° C. for up to 2 months.Stability of the product is assessed by testing periodically forgranisetron content and the total amount of impurities using highperformance liquid chromatography. The results are shown below in Table3. TABLE 3 Total impurities Granisetron Potency (% of granisetron) (%w/w) Formu- Time Formulation C Formulation D lation C Formulation DT_(o) 99.9 99.5 0.05 0.25 1 month at 99.8 99.2 0.12 0.41 50° C. 2 monthat 99.6 98.4 0.19 0.81 50° C.

The data in Table 3 show that the granisetron remains stable for atleast 2 months at 50° C. in the composition of the example of theinvention with little loss of granisetron potency and low amounts ofimpurities relative to the formulations at starting time T_(o).

EXAMPLE 4 Samples for in vivo Test

Patches were made according to the method described above using theingredients and respective amounts shown in Table 4. Weight % Wt infinished product Ingredient/Component (mg/cm²) Composition (mg/25 cm²patch) Granisetron base 0.75 2.54 18.75 Isopropyl myristate 1.20 4.0630.00 Acrylic adhesive 13.05 44.13 326.25 Total 15.00 50.73 375.00Polyester backing 3.91 13.22 97.75 Release liner 10.66 36.05 266.50Total weight 29.57 100.00 739.25

The acrylic adhesive used in Example 4 was DURO-TAK®87-2516, availablefrom National Starch and Chemical in Bridgewater, N.J.

A randomized crossover clinical study was conducted in 11 individualswho received either a transdermal patch or an IV solution ofgranisetron. Each 25 cm² patch was formulated to deliver 2 mg/day ofgranisetron. The 25 cm² patches of Example 4 were applied to the skin ofindividuals and left in place for 96 hours, at which time they wereremoved. This was followed by a 10 day wash-out period, after which thesame individuals received granisetron IV in once-daily dosages of 2mg/day Individuals who received the IV treatment in the first periodreceived a transdermal patch in the cross over treatment. Blood plasmalevels of granisetron for all of the individuals in the test weremeasured periodically during the 96 hour time that the patches werebeing worn and the IV dosages were being administered, and for anadditional 2 days after the patches were removed and the IVadministration discontinued.

The results (FIG. 3A) indicated that the individuals receiving IVgranisetron experienced sharp spikes in blood plasma levels of thegranisetron after each daily dose was administered and the blood plasmalevels decreased very quickly. On the other hand, the blood plasmalevels of granisetron in the individuals wearing the patches increasedsteadily and reached a plateau that was maintained until the patcheswere removed after 96 hours, at which time the blood plasma levelsdecreased slowly and steadily, while still remaining in thetherapeutically effective range for more than 24 hours after the patcheswere removed. With granisetron, typical plasma levels were observed tobe in the range of 0.1-25 ng/ml over the whole wear time and for twoadditional days following patch removal. Thus, the patch of this exampleprovided a blood plasma level in a therapeutically effective range bothfor the entire patch wear time and for more than 24 hours after it wasremoved.

Publications and references, including but not limited to patents andpatent applications, cited in this specification are herein incorporatedby reference in their entirety in the entire portion cited as if eachindividual publication or reference were specifically and individuallyindicated to be incorporated by reference herein as being fully setforth. Any patent application to which this application claims priorityis also incorporated by reference herein in the manner described abovefor publications and references.

While this invention has been described with an emphasis upon certainembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

1. A method of treating acute, delayed or anticipatory emesis for asustained period in an individual, the method comprising: applying to aportion of intact skin or mucosa on the individual for 24 hours or morea composition comprising: i. an antiemetically effective amount of a5-HT₃ receptor antagonist; ii. a permeation enhancing amount ofpermeation enhancer comprising 0.5% to 15% by weight of theskin-contacting layer; and iii. an adhesive, wherein a plasmaconcentration of the 5-HT₃ receptor antagonist in a therapeuticallyeffective range is provided for period of time from an onset time to 12hours or more after the composition is removed.
 2. The method of claim1, wherein, 12 or more hours after removing the composition, applying toa portion of intact skin or mucosa on the individual a second saidcomposition, wherein a plasma concentration of the 5-HT₃ receptorantagonist in a therapeutically effective range is provided for periodof time from an onset time to 12 hours or more after the second saidcomposition is removed.
 3. The method of claim 1, further comprisingadministering an antiemetically effective amount of a corticosteroid. 4.The method of claim 3, wherein the corticosteroid is administeredtransdermally.
 5. The method of claim 3, wherein the corticosteroid isadministered orally or by injection.
 6. The method of claim 1, furthercomprising administering an antiemetically effective amount of anantiemetic agent in a second dosage form.
 7. The method of claim 1,wherein the serotonin 5-HT₃ receptor antagonist is selected from thegroup consisting of ondansetron, granisetron, tropisetron, dolasetron,hydrodolasetron, azasetron, ramosetron, lerisetron, indisetron,itasetron, palonosetron, lamosetron, allosetron, and mixtures thereof.8. The method of claim 1, wherein the 5-HT₃ receptor antagonist isgranisetron.
 9. The method of claim 8, further comprising administeringan antiemetically effective amount of a corticosteroid.
 10. The methodof claim 1, wherein the permeation enhancer consists essentially of 15%or less by weight of the skin-contacting layer of a fatty acid ester offatty acyl chain length C₁₂-C₁₈, or mixtures thereof.
 11. The method ofclaim 1, wherein the permeation enhancer consists essentially of 15% orless by weight of the skin-contacting layer of isopropyl myristate. 12.The method of claim 1, further comprising the step of, in coordinationwith said applying, administering to the individual a pharmaceutical orprocedure that creates a risk of emesis.
 13. The method of claim 12,wherein said applying occurs prior to said enesis risk-creatingadministration.
 14. A composition for transdermal administration of anantiemetic comprising: a skin-contacting composition comprising: i. anantiemetically effective amount of a 5-HT₃ receptor antagonist; ii. apermeation enhancing amount of permeation enhancer comprising 0.5% to15% by weight of the skin-contacting layer; and iii. an adhesive,wherein, when applied to a portion of intact skin on an individual for24 hours and then removed, the composition provides the individual witha plasma concentration of the 5-HT₃ receptor antagonist in atherapeutically effective range for period of time from an onset time to12 hours or more after the composition is removed.
 15. A device fortransdermal prevention, amelioration or treatment of nausea and vomitingin an individual which comprises a patch comprising: a. a support layer;and b. a skin-contacting layer comprising: i. an antiemeticallyeffective amount of a 5-HT₃ receptor antagonist; ii. a permeationenhancing amount of permeation enhancer comprising 0.5% to 15% by weightof the skin-contacting layer; and iii. an adhesive, wherein, whenapplied to a portion of intact skin on an individual for 24 hours andthen removed, the device provides the individual with a plasmaconcentration of the 5-HT₃ receptor antagonist in a therapeuticallyeffective range for period of time from an onset time to 12 hours ormore after the device is removed.
 16. The device of claim 15, wherein,when applied to a portion of intact skin on an individual for 48 hoursand then removed, the device provides the individual with a plasmaconcentration of the 5-HT₃ receptor antagonist in a therapeuticallyeffective range for period of time from an onset time to 12 hours ormore after the device is removed.
 17. The device of claim 15, wherein,when applied to a portion of intact skin on an individual for 72 hoursand then removed, the device provides the individual with a plasmaconcentration of the 5-HT₃ receptor antagonist in a therapeuticallyeffective range for period of time from an onset time to 12 hours ormore after the device is removed.
 18. The device of claim 15, wherein,when applied to a portion of intact skin on an individual for 96 hoursand then removed, the device provides the individual with a plasmaconcentration of the 5-HT₃ receptor antagonist in a therapeuticallyeffective range for period of time from an onset time to 12 hours ormore after the device is removed.
 19. The device of claim 15, whereinthe 5-HT₃ receptor antagonist is in free base form.
 20. A kit comprisingthe device of claim 15, and a dosage form comprising an antiemeticallyeffective amount of a corticosteroid.
 21. The kit of claim 20, whereinthe dosage form is for oral administration or injection of thecorticosteroid.
 22. The kit of claim 20, wherein the dosage form is fortransdermal administration of the corticosteroid.
 23. A kit comprisingthe device of claim 15, and a dosage form comprising antiemetic agent(s)in forms adapted for oral administration or injection.
 24. The kit ofclaim 23, wherein the agent of the dosage form is a 5-HT₃ receptorantagonist, cannabinoid, NK1 receptor antagonist, dopamine antagonist,corticosteroid, or mixture thereof.
 25. The device of claim 15, whereinthe 5-HT₃ receptor antagonist is selected from the group consisting ofondansetron, granisetron, tropisetron, dolasetron, hydrodolasetron,azasetron, ramosetron, lerisetron, indisetron, itasetron, palonosetron,lamosetron, allosetron, and mixtures thereof.
 26. The device of claim15, wherein the 5-HT₃ receptor antagonist is granisetron.
 27. The deviceof claim 26, wherein the antiemetically effective amount of granisetroncomprises between 0.1% and 15% by weight of the skin-contacting layer.28. The device of claim 15, wherein the permeation enhancer consistsessentially of 15% or less by weight of the skin-contacting layer of afatty acid ester of fatty acyl chain length C₁₂-C₁₈, or mixturesthereof.
 29. The device of claim 15, wherein the permeation enhancerconsists essentially of 15% or less by weight of the skin-contactinglayer of isopropyl myristate.
 30. The device of claim 15, furthercomprising packaging presenting labeling describing applying the deviceto an individual in conjunction with one or both of (a) administrationto the individual of a pharmaceutical that creates a risk of emesis or(b) implementing on the individual an operative or other medicalprocedure that creates a risk of emesis.
 31. The device of claim 30,wherein the labeling describes applying the device 30 minutes or moreprior to the administration or implementing.
 32. The device of claim 15,wherein the device, when applied to a portion of human cadaver skin for168 hours or more, provides a flux rate of between 1 and 25 μg/cm²/hr,the flux rate remaining between 1 and 25 μg/cm²/hr for 168 hours ormore.
 33. The device of claim 15, wherein the device, when applied to aportion of intact skin on an individual for 168 hours, delivers between10 and 10,000 μg/day of the 5-HT3 receptor antagonist to the individualfor each day after an onset period.
 34. The device of claim 15, whereinthe device, when applied to a portion of intact skin on an individualfor a period from 24 hours to 144 hours and then removed, deliversbetween 10 and 10,000 μg/day of the 5-HT3 receptor antagonist to theindividual for each day after an onset period through 12 hours afterremoval.